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In April 2018, the Clinical Trials Act pertaining to investigator-initiated clinical trials was passed in Japan. The purpose of this study was to investigate activity in investigator-initiated clinical studies before and after enforcement of the new Clinical Trials Act. This was done by analysing the records of the Ethics Committee of Tokushima University Hospital, which reviews studies based on the Japanese government's Ethical Guidelines for Medical and Health Research Involving Human Subjects prior to the Clinical Trials Act, and records of the Certified Review Board established at Tokushima University under the Clinical Trials Act in 2018. The number of new applications to these two review boards during fiscal years 2015-2017 (pre-Act) and fiscal years 2018 and 2019 (post-Act) were used as an indicator of activity in investigator-initiated clinical studies. The number of new applications to the Ethics Committee was 303, 261, 316, 303, and 249 in 2015, 2016, 2017, 2018, and 2019, respectively. The data show that the total number of new interventional studies decreased from 50.3 in average in 2015-2017 (pre-Act) to 42 in 2018 and 40 in 2019 (post-Act), respectively. These results suggest that fewer interventional studies were started following enforcement of the new Clinical Trials Act. To confirm this trend and identify contributing factors, further studies are required. In addition, possible way, such as broader contribution of clinical research coordinators, to promote clinical studies in the new Clinical Trials Act era should be examined.

The role of research ethics consultants in biomedical research has increased to the point that they have an advisory capacity at all research institutes. For such professionals, we have established an educational system, which includes teaching materials, training methods, and nationwide educational workshops. These workshops have served to examine the developed system’s usefulness and to provide realistic training for consultant candidates. In addition, we have used the current workshop to encourage clinical research investigators (and related personnel) to participate. Subsequently, we examined its usefulness as an opportunity to provide exposure to research ethics. In October 2019, we held a 1-day pilot workshop in Tokushima, Japan, which included a basic lecture in research ethics. During the lecture, two sets of materials were used for case discussion: case 1, covering issues related to a clinical trial, and case 2, covering issues related to human biological specimens. At the end of the workshop, a 30-item self-reporting anonymous questionnaire was provided. Of the 13 total participants, 9 (70%) were clinical research investigators and related personnel, while 6 (46%) had no direct intention to act as consultants. Respondents indicated that case 2 was more difficult than case 1. However, both cases were generally accepted as educational materials; thus, satisfaction was expressed in relation to both. As the evaluations of the cases were generally positive, we will further examine the usefulness of participation in the workshop in the cultivation of research ethics in the investigator community.

Background : Enforcement of the 2018 Clinical Trials Act (CTA) in Japan resulted in strict and complicated regulations surrounding intervention studies. Few Japan-specific measures have been developed to promote intervention studies in Japan despite concerns about CTA's negative influence on such studies. Therefore, this study examined the changes in academic investigators' interest in conducting clinical studies before and after enforcement of the CTA to determine measures to promote specified clinical trials. Methods : We conducted a questionnaire survey with investigators belonging to the Institute of Biomedical Sciences, Tokushima University Graduate School, before and after enforcement of the CTA. Results : Investigators had lesser interest in intervention studies in the post-questionnaire survey (post) group than in the pre-questionnaire survey (pre) group. Their desire for "project management" was significantly higher in the post-group than in the pre-group. Their desire for "support for preparing documents when conducting specified clinical trials" was significantly higher in the group interested in conducting specified clinical trials than that in the not-interested group. Conclusion : We revealed that investigators were highly interested in "project management" and "support for preparing documents when conducting specified clinical trials" after enforcement of the CTA. Measures for these desires may promote specified clinical trials. J. Med. Invest. 68 : 71-75, February, 2021.

Background With the global proliferation of the novel COVID-19 disease, conventionally conducting institutional review board (IRB) meetings has become a difficult task. Amid concerns about the suspension of drug development due to delays within IRBs, it has been suggested that IRB meetings should be temporarily conducted via the internet. Objective This study aimed to elucidate the current status of IRB meetings conducted through web conference systems. Methods A survey on conducting IRB meetings through web conference systems was administered to Japanese national university hospitals. Respondents were in charge of operating IRB offices at different universities. This study was not a randomized controlled trial. Results The survey was performed at 42 facilities between the end of May and early June, 2020, immediately after the state of emergency was lifted in Japan. The survey yielded a response rate of 74% (31/42). Additionally, while 68% (21/31) of facilities introduced web conference systems for IRB meetings, 13% (4/31) of the surveyed facilities postponed IRB meetings. Therefore, we conducted a further survey of 21 facilities that implemented web conference systems for IRB meetings. According to 71% (15/21) of the respondents, there was no financial burden for implementing these systems, as they were free of charge. In 90% (19/21) of the facilities, IRB meetings through web conference systems were already being conducted with personal electronic devices. Furthermore, in 48% (10/21) of facilities, a web conference system was used in conjunction with face-to-face meetings. Conclusions Due to the COVID-19 pandemic, the number of reviews in clinical trial core hospitals has decreased. This suggests that the development of pharmaceuticals has stagnated because of COVID-19. According to 71% (15/21) of the respondents who conducted IRB meetings through web conference systems, the cost of introducing such meetings was US $0, showing a negligible financial burden. Moreover, it was shown that online deliberations could be carried out in the same manner as face-to-face meetings, as 86% (18/21) of facilities stated that the number of comments made by board members did not change. To improve the quality of IRB meetings conducted through web conference systems, it is necessary to further examine camera use and the content displayed on members’ screens during meetings. Further examination of all members who use web conference systems is required. Our measures for addressing the requests and problems identified in our study could potentially be considered protocols for future IRB meetings, when the COVID-19 pandemic has passed and face-to-face meetings are possible again. This study also highlights the importance of developing web conference systems for IRB meetings to respond to future unforeseen pandemics.

BACKGROUND With the global proliferation of the novel COVID-19 disease, conventionally conducting institutional review board (IRB) meetings has become a difficult task. Amid concerns about the suspension of drug development due to delays within IRBs, it has been suggested that IRB meetings should be temporarily conducted via the internet. OBJECTIVE This study aimed to elucidate the current status of IRB meetings conducted through web conference systems. METHODS A survey on conducting IRB meetings through web conference systems was administered to Japanese national university hospitals. Respondents were in charge of operating IRB offices at different universities. This study was not a randomized controlled trial. RESULTS The survey was performed at 42 facilities between the end of May and early June, 2020, immediately after the state of emergency was lifted in Japan. The survey yielded a response rate of 74% (31/42). Additionally, while 68% (21/31) of facilities introduced web conference systems for IRB meetings, 13% (4/31) of the surveyed facilities postponed IRB meetings. Therefore, we conducted a further survey of 21 facilities that implemented web conference systems for IRB meetings. According to 71% (15/21) of the respondents, there was no financial burden for implementing these systems, as they were free of charge. In 90% (19/21) of the facilities, IRB meetings through web conference systems were already being conducted with personal electronic devices. Furthermore, in 48% (10/21) of facilities, a web conference system was used in conjunction with face-to-face meetings. CONCLUSIONS Due to the COVID-19 pandemic, the number of reviews in clinical trial core hospitals has decreased. This suggests that the development of pharmaceuticals has stagnated because of COVID-19. According to 71% (15/21) of the respondents who conducted IRB meetings through web conference systems, the cost of introducing such meetings was US $0, showing a negligible financial burden. Moreover, it was shown that online deliberations could be carried out in the same manner as face-to-face meetings, as 86% (18/21) of facilities stated that the number of comments made by board members did not change. To improve the quality of IRB meetings conducted through web conference systems, it is necessary to further examine camera use and the content displayed on members’ screens during meetings. Further examination of all members who use web conference systems is required. Our measures for addressing the requests and problems identified in our study could potentially be considered protocols for future IRB meetings, when the COVID-19 pandemic has passed and face-to-face meetings are possible again. This study also highlights the importance of developing web conference systems for IRB meetings to respond to future unforeseen pandemics.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the upper and lower motor neurons. Currently, only riluzole and edaravone are approved as drugs to treat ALS and new agents with larger effect sizes are warranted. Exploratory analyses in our previous study (study ID #E0302-J081-761) have suggested that high-dose methylcobalamin (E0302) prolonged the overall survival of ALS patients and suppressed ALS progression in patients with a disease duration of less than 12 months. Objective: This clinical trial aims to evaluate the efficacy and safety of E0302 for treatment of ALS patients within one year of onset. Methods: The Japanese early-stage trial of high-dose methylcobalamin for ALS (JETALS) is a prospective, multicenter, placebo-controlled, double-blind, randomized phase III study conducted at 24 tertiary neurology centers and is funded by the Japan Agency for Medical Research and Development. A total of 128 ALS patients within one year of onset were randomized at a 1:1 ratio to receive intramuscular injection with E0302 50 mg or placebo twice a week for 16 weeks. The primary endpoint is changes in the ALS Functional Rating Scale-Revised (ALSFRS-R) total score at 16 weeks. If patients wish to receive E0302 50 mg after the double-blind administration period, E0302 will be provided to them until March 2020 during the continuous administration period. Results: This study began in October 2017 and is being conducted at 24 participating institutions in Japan. The study is in progress and the patient enrollment period is scheduled to end in August 2019, with follow-up scheduled to end in March 2020. Conclusions: This study is being performed to revalidate the efficacy and safety of E0302 in patients with early-stage ALS in the first year of symptom onset. If positive results are obtained, the aim is to apply for E0302 approval as a new drug for the treatment of ALS. Trial Registration: ClinicalTrials.gov NCT03548311; https://clinicaltrials.gov/ct2/show/NCT03548311 (Archived by WebCite at http://www.webcitation.org/74Fw3rDzb) International Registered Report Identifier (IRRID): PRR1-10.2196/12046

We report a follicular lymphoma (FL) case presenting the coexistence of two tumor cell subpopulations in lymph node (LN) and bone marrow (BM), which exhibited an inverse pattern of immunoglobulin light (IgL) chain gene rearrangement and expression: Igkappa-lambda+ in LN and Igkappa+lambda- in BM. These tumor clones shared an identical BCL2-IgH recombination, accompanying t(14;18)(q32;q21) translocation, and an identical variable, diversity and joining segments joining with clone-specific VH somatic hypermutations on the untranslocated IgH allele. Our study provides further evidence that FL clones, originating from common progenitor cells, can be developed independently at different sites and with different IgL expression after immune selection.

Nicotine is a major alkaloid accumulating in the vacuole of tobacco (Nicotiana tabacum), but the transporters involved in the vacuolar sequestration are not known. We here report that tobacco genes (NtMATE1 and NtMATE2) encoding transporters of the multidrug and toxic compound extrusion (MATE) family are coordinately regulated with structural genes for nicotine biosynthesis in the root, with respect to spatial expression patterns, regulation by NIC regulatory loci, and induction by methyl jasmonate. Subcellular fractionation, immunogold electron microscopy, and expression of a green fluorescent protein fusion protein all suggested that these transporters are localized to the vacuolar membrane. Reduced expression of the transporters rendered tobacco plants more sensitive to the application of nicotine. In contrast, overexpression of NtMATE1 in cultured tobacco cells induced strong acidification of the cytoplasm after jasmonate elicitation or after the addition of nicotine under nonelicited conditions. Expression of NtMATE1 in yeast (Saccharomyces cerevisiae) cells compromised the accumulation of exogenously supplied nicotine into the yeast cells. The results imply that these MATE-type proteins transport tobacco alkaloids from the cytosol into the vacuole in exchange for protons in alkaloid-synthesizing root cells.

A 60-year-old man was admitted with muscle weakness and numbness in the extremities. Based on the existence of monoclonal gammopathy of the IgG-lamda type, a slight increase of plasma cells in the bone marrow, and an elevated level of serum vascular endothelial growth factor (VEGF), the diagnosis of POEMS syndrome was made. After peripheral blood stem cell collection by etoposide and G-CSF, the patient received high dose melphalan (200 mg/m2) therapy supported by autologous peripheral blood stem cell transplantation (autoPBSCT). After high-dose chemotherapy with autoPBSCT, the serum VEGF level normalized and the monoclonal IgG-lamda, disappeared. The patient gradually recovered from a bedridden state and at the time of writing has no impairment in his activities of daily life. After the autoPBSCT, monoclonal IgG-kappa, protein was detected transiently in serum. The new monoclonal immunoglobulin was considered to be due to normal immune reconstitution after myeloablation rather than alteration of the abnormal plasma cell clone, similarly as oligoclonal immunoglobulins occur in multiple myeloma after autoPBSCT. AutoPBSCT with high-dose chemotherapy should be considered among the treatments of choice for POEMS syndrome.

A 62-year-old woman was admitted to our hospital because of gastric mucosal bleeding. Gastroendoscopy revealed a gastric tumor which was diagnosed from the biopsied specimen as diffuse large B-cell lymphoma (DLBCL). Lymphoma cells had infiltrated the bone marrow showed morphological features resembling Burkitt lymphoma (BL). Nearly 100% of the cells in the bone marrow were positive for MIB-1 immunostaining. The chromosomal study was normal. Surface marker analysis disclosed that the cells were positive for CD10, CD19, CD20 and CD25. As lymphoma cells had infiltrated the central nervous system, combined chemotherapy was performed accompanied with intrathecal administration of anticancer drugs. Although transient improvement was observed, the patient died of the advanced disease three months after admission. As we have shown here, there are some cases of DLBCL with immunohistochemical features resembling BL. Further consideration about the appropriate chemotherapy program for this type of disease might be necessary.

A 61-year-old man with primary macroglobulinemia (PMG) had been followed without any treatment as he had no apparent manifestations. After 1 year and 3 months, he was admitted to our hospital with a fever. No signs or symptoms of infection and no progressive increase of serum IgM levels was observed. Non-Hodgkin's lymphoma was not additionally found. Fever without infection, elevated serum LDH level and further enlargement of the spleen compelled us to diagnose his condition as deterioration of the PMG. An immediate fall in his temperature and serum IgM levels was observed after CHOP therapy. Effective therapy must be discussed in the deterioration of this type of disease.

This study estimates the effect of creases, or plastic wrinkle lines, on the out-of-plane stiffness of solar sails. A method to simulate the crease effects using reduced-order finite-element (FE) models is proposed, and is applied to a practical solar sail architecture. A detailed crease shape is determined by a geometrically nonlinear FE analysis using a simple model first; the effect of creases is then replaced by beam elements. This method substantially reduces the computational effort required for the FE analysis of a solar sail model. The result suggests the significant impact of creases on membrane's out-of-plane stiffness when the tension level in the membrane is small., 資料番号: PA1510010000

During hemodialysis session plasma glucose decreases steeply, and then increases to hyperglycemic state afterwards in diabetic hemodialysis patients. IDeg, engineered acylated insulin, was recently reported to form a soluble depot after subcutaneous injection with a subsequent slow release of insulin and an ultralong glucose-lowering and stabilizing effect.